Regulation of immune cell metabolism in aging and Alzheimer's disease: role of the kynurenine pathway Abstract Aging, the major risk factor for development of Alzheimer's disease (AD), is characterized by a progressive decline in immune function, with changes in cellular and humoral responses and phagocytic potential and increased generation of pro-inflammatory mediators. Recent GWAS and systems biology studies have demonstrated that a disrupted innate immune response is a dominant risk factor for development of AD. A second feature of aging and AD is a marked decline in cellular bioenergetics and metabolism. The coordinated decline of both mitochondrial and immune functions with aging suggests that worsening cellular bioenergetics may drive development of maladaptive immune responses. Defining the mechanisms that underlie this interaction may help identify molecular pathways that could simultaneously restore healthy mitochondrial metabolism and immune function for prevention and treatment of AD. In recent studies, wehave examined the function of the kynurenine pathway (KP) in myeloid cells, including microglia and peripheral macrophages cells. The immune KP is a catabolic pathway wherein the essential amino acid tryptophan is metabolized to kynurenine (KYN) by the rate-limiting enzyme indole-2,3-dioxygenase-1 (IDO1). KYN is then metabolized down the KP to the neuroactive compound quinolinic acid (QA), which is an NMDA receptor agonist. Interestingly, QA is a precursor of NAD+ and the KP is the sole source of de novo NAD+ production. We hypothesize that the KP plays an important role in replenishing NAD+ in contexts of immune cell activation and in aging, and particularly in the context of accumulating A peptides, which is a necessary step in the progression to AD. Experiments proposed will test the function of the KP and de novo NAD+ generation in microglial and macrophage metabolism and immune functions in models of aging and AD. We will use complementary genetic and pharmacologic approaches in vitro in primary myeloid cells and in vivo in novel mouse transgenic and conditional knockout lines. The proposed studies will determine whether the KP performs a critical function at the intersection of immune cell metabolism and function and whether enhancing KP activity can restore immune functions that are lost in aging and neurodegenerative disease.